DESCRIPTION: Flavoproteins constitute one of the largest groups of functionall related proteins currently known, catalyzing essential oxidation/reduction steps in almost every metabolic pathway in both prokaryotic and eukaryotic cells. Using essentially the same riboflavin-based cofactor, flavoproteins participate in a remarkable array of biological processes, from simple electro transfer to complex signal transduction pathways. Flavoproteins are also uniqu in facilitating electron transfer between obligatory one- and two-electron donor and acceptor molecules such as between pyridine nucleotides and heme-containing proteins. It is not surprising, then, that defects within thes critical electron transfer processes may manifest themselves in severe, and sometimes fatal, metabolic diseases. The principal long term goal of this research is to understand more thoroughly the fundamental factors that control or modulate the oxidation-reduction properties and chemical reactivity of the bound flavin cofactor in these proteins. Our efforts are primarily focused on the role of specific molecular interactions between cofactor and proteinCboth short and long rangeCand protein conformational changes in the regulation (of) the oxidation-reduction potentials of the flavin, a central factor in electron transfer and reactivity. A secondary research goal is the evaluation of protei structural features that are crucial in facilitating electron transfer by way of the flavin cofactor between redox centers/proteins. The flavodoxin has been our principal model system of study and may serve as one paradigm for FMN-binding domains in complex flavoproteins such as cytochrome P450 reductase and nitric oxide synthase. These flavoproteins catalyze important reactions in fatty acid metabolism; xenobiotic, steroid and prostaglandin biosynthesis; and in neurotransmission. Blood pressure homeostasis, and inflammatory responses. second system under study, the electron transfer flavoprotein, provides a different type of flavin binding site with unique structure and properties distinct from the flavodoxin. This proposal describes the continuation of the development of a biochemical model and underlying concepts for the regulation of the reduction potentials and, secondarily, electron transfer in the flavodoxin and the electron transfer flavoprotein, ultimately leading to a greater general understanding of these processes in other flavoproteins.